Poison-Center Data: Major Bleeding 'Rare' After Overdose of Factor Xa Inhibitors

Deborah Brauser

September 25, 2015

COLUMBUS, OH — Overingestion of two factor Xa inhibitors is rarely associated with serious bleeding in adults — and has no association with toxicity in kids who accidently take the drugs, suggests new research[1].

A retrospective, observational study of data from poison-control centers showed that among the 198 patients who ingested the novel oral anticoagulant (NOAC) rivaroxaban (Xarelto, Bayer/Janssen Pharmaceuticals), prothrombin time (PT) and partial thromboplastin time (PTT) were elevated in only seven and five of the participants, respectively. Although bleeding events were reported by 11 of the rivaroxaban-taking patients, all occurred after long-term use.

Among the 25 participants who took the NOAC apixaban (Eliquis, Bristol Myers-Squibb), there were no elevations in PT and PTT, and four cases of bleeding, although, as with rivaroxaban, only after long-term ingestion.

In addition, there was no abnormal coagulation or reports of bleeding among the children who took either apixaban or rivaroxaban just once.

Lead author Henry A Spiller (Central Ohio Poison Center and Nationwide Children's Hospital, Columbus, OH) told heartwire from Medscape that he was pleasantly surprised at the low number of serious complications that occurred in this study.

"We wanted to see if there were a lot of cases of bleeding, and there really weren't. The bleeding that we did see was relatively minor, except in one case where a patient was anticoagulated, fell, and had a cerebral hemorrhage," said Spiller. Other than that, the fairly positive results "were good to know, because these are fairly widely used drugs."

The findings were published in the Annals of Emergency Medicine.

Investigating Toxicology

The investigators note that data are limited when it comes to dosing or overdosing with rivaroxaban, and overdosing literature is nonexistent for apixaban.

Although serious bleeding is a potential risk with anticoagulants, Xa inhibitors "appear to have a ceiling effect based on saturation binding of factor Xa sites," they write. This is different from warfarin, which targets vitamin-K–dependent factors, and the direct thrombin inhibitor dabigatran ( Pradaxa, Boehringer Ingelheim).

"This is a new class of drugs, and when new drugs come out, there often isn't a whole lot of toxicology information on them—especially if there is a new mechanism," said Spiller. "There may be therapeutic clinical trials, but what do we see in the real world when you start having four million people on it? So we thought it important to look into this."

The investigators evaluated data from eight poison centers in the US on cases of single-substance ingestion of Xa inhibitors for 223 patients (56% female; mean age 60 years). The study population included 20 children under the age of 12 years.

Among the patients who took rivaroxaban, the mean dose was 64.5 mg (range 5–1200 mg), although the recommended daily dose is 10–20 mg. The mean dose for those taking apixaban was 9.6 mg (range 2.5–20 mg); its recommended dose is 2.5–5 mg twice daily.

In the rivaroxaban group, 13 of the 61 patients who had international normalized ratio (INR) measured showed elevation, whereas elevation was found in none of the five apixaban patients who had INR measurements.

Among the 15 patients who reported incidents of bleeding, eight of the sites were gastrointestinal, two were oral, two were nose, and one each were for bruising/intravenous, urine, and subdural after a fall with a head injury.

"Coagulation test results were normal in most patients with bleeding: [PT] in five of six (83%); [PTT] in five of six (83%); and [INR] in five of nine (55%)," report the researchers.

"Not a Lot of Bleeding"

There were also 12 suicide attempts using prescribed rivaroxaban in large doses. There were no drug-related bleeding events, but altered coagulation occurred in five of these patients.

Finally, hepatic transaminase levels were elevated higher than 1000 U/L in two patients in the rivaroxaban group, a 25-year-old man with hepatitis C and an 82-year-old man with deep vein thrombosis (DVT).

"Bleeding after Xa inhibitor ingestion as a single agent is uncommon," write the investigators. However, "massive acute ingestion in suicide attempt may result in significant anticoagulation."

Spiller noted that when patients comes into the emergency department for any reason, and not just for drug-related incidents, it's important to know if they are taking a drug that causes bleeding before moving on to setting bones, etc. When asked if he thought there's a need for Xa reversal agents in this setting, Spiller answered, "Maybe."

"There are a few in the pipeline. And there may be some cases where you need to reverse it, particularly if you have an emergent need for an invasive procedure," he said.

Spiller said that the study's take-away messages are that "we didn't see a whole lot of bleeding, which was nice," and the common tests of PT, PTT, and INR "may not necessarily be reliable." In addition, he noted that although there were only two cases of hepatic injury, that's a significant enough adverse event that anyone on this drug class for a period of time should be tested for changes in liver function at least once.

As for kids, Spiller said the investigators wanted to see if taking one or two of these drugs belonging to a family member would put them in danger. "And the answer is: probably not." However, he noted that parents should go ahead and call their local poison center if that occurs. That will provide a rapid answer based on the particular circumstances, including weight of the child, dose taken, etc.

Reassuring and Encouraging

"I thought this study was reassuring. These are new drugs that we know are potent anticoagulants; and we know from the big trials that the major side effect is bleeding," Dr Joseph S Alpert (University of Arizona Sarver Heart Center, Tucson) told heartwire .

"You wonder: what happens if a kid gets into it or if someone forgets and takes three pills instead of one? So it was encouraging that, at least acutely, there wasn't a huge problem," said Alpert, who was not involved with this research.

He noted that clinicians should still tell patients to be careful to take the right dosage and to keep their pills away from children. "But know in the back of your mind that, at least with this small experience, there wasn't bad bleeding. Not that patients shouldn't always be careful, but at least this gives us a little leeway of safety."

Still, Alpert agreed with Spiller's recommendation that liver screens should be given to these patients. "With almost any drug, some people will have some liver toxicity. So anytime you start a new drug, it's always worthwhile to check liver function after a few months."

He added that this is commonly done with statins. "It's perfectly reasonable to do the same thing with these drugs."

Alpert also noted that although he'd like to see bigger studies of this conducted in the future, "this report is a reassuring first step."

The study authors report no relevant financial relationships. Alpert reports having been chair of the data safety and monitoring committee for two rivaroxaban trials: ROCKET-AF and PIONEER, and receiving payment from Bayer and Johnson & Johnson.


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